- Awarded: 2017
- Award Type: Research
- Award #: 514863
The subunits of the switch/sucrose non-fermentable (i.e., BAF or SWI/SNF) complex are among the most commonly mutated genes in human neurodevelopmental disease and include disorders along the autism spectrum (ASD). BAF complexes regulate chromatin structure in an ATP-dependent fashion. The underlying mechanism by which mutations in BAF subunits contribute to neuronal pathophysiology is unknown.
Gerald Crabtree’s laboratory studies developmental mechanisms of chromatin remodeling under the control of subunit-specific BAF complexes. Joseph Gleeson’s lab studies genetic forms of ASD where mutations in the BAF complex components have emerged as an important cause. Crabtree and Gleeson propose to study competition between the BAF complex and the Polycomb repressor complex 2 (PRC2) in the regulation of activity-dependent gene transcription. From a cohort of individuals with recessive forms of ASD, Crabtree and Gleeson screened for mutations in the BAF complex, identifying several with mutations in neural specific components. Their preliminary data suggests evolutionary conservation of function for these neural-specific complexes in mediating gene transcription and chromatin architecture in an activity-dependent fashion.
Crabtree and Gleeson now propose to use human induced pluripotent stem cells carrying specific mutations derived from individuals with ASD, in combination with knockout mice, to study activity-dependent gene transcription, chromatin architecture and single-cell profiling in the absence of BAF subunits. An important question is whether there is redundancy between subunits within the complex, which can rescue altered transcriptional changes in the mutant state. This proposal brings together two established research teams, with complementary expertise, to study the mechanisms of chromatin remodeling in the pathophysiology of ASD.